Abstract
One activity potentially limiting the efficacy of camptothecin anticancer agents is their cellular efflux by the ATP-binding cassette half-transporter, ABCG2. Homocamptothecins are novel anticancer drugs that inhibit topoisomerase 1 with a greater potency than camptothecins. Homocamptothecins differ from camptothecins by their E-ring, which is seven-membered instead of the six-membered ring of camptothecins. We report herein that, like camptothecins, homocamptothecin and its difluoro derivative BN80915 are substrates for ABCG2. However, the resistance of three selected cell lines overexpressing wild-type or mutant ABCG2 to homocamptothecin or BN80915 was less than resistance to SN-38 (7-ethyl-10-hydroxycamptothecin), indicating that both the seven-membered E-ring present in homocamptothecin and the A- and B-ring modifications present in SN-38 are involved in substrate recognition by ABCG2. HEK-293 cells transfected with vectors encoding wild-type or mutant ABCG2 were found to be less resistant to both homocamptothecins than to SN-38. However, transfectants overexpressing mutant ABCG2 had relative resistance values for homocamptothecin and BN80915 4- to 14-fold higher than cells expressing wild-type ABCG2, suggesting that the gain of function resulting from mutation at amino acid 482, although not affecting SN-38, extends to the homocamptothecins. Resistance was reversed by the ABCG2 inhibitor fumitremorgin C. BN80915 was 17-fold more potent than SN-38 in wild-type ABCG2-transfected cells, suggesting that BN80915 has the potential to overcome ABCG2-related resistance to SN-38, the active metabolite of CPT-11 (irinotecan).
Footnotes
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DOI: 10.1124/jpet.103.063149.
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ABBREVIATIONS: CPT, camptothecin; Top1, topoisomerase 1; SN-38, 7-ethyl-10-hydroxycamptothecin; BN80915, difluorocamptothecin; FTC, fumitremorgin C; HEK-293, human embryonic kidney cells; bp, base pair(s); RR, relative resistance; DMF, dose-modifying factor; hCPT, homocamptothecin.
- Accepted March 16, 2004.
- Received November 20, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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